The present invention relates to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More particularly, this invention concerns bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane substituted tetrahydro-2H-pyran-2-ones and the corresponding ring-opened acids derived therefrom which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), pharmaceutical compositions containing such compounds, and a method of lowering blood serum cholesterol levels employing such pharmaceutical compositions.
High levels of blood cholesterol and blood lipids are conditions which are involved in the onset of arteriosclerosis. It is well known that inhibitors of HMG-CoA reductase are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C), in man (cf. M. S. Brown and J. L. Goldstein, New England Journal of Medicine (1981), 305, No. 9, 515-517). It has now been established that lowering LDL-C levels affords protection from coronary heart disease (cf. Journal of the American Medical Association (1984) 251, No. 3, 351-374).
Moreover, it is known that certain derivatives of mevalonic acid (3,5-dihydroxy-3-methylpentanoic acid) and the corresponding ring-closed lactone form, mevalonolactone, inhibit the biosynthesis of cholesterol (cf. F. M. Singer, et al, Proc. Soc. Exper. Biol. Med. (1959), 102, 370-373) and F. H. Hulcher, Arch. Biocchem. Biophys. 30 (1971), 146, 422.
U.S. Pat. Nos. 3,983,140; 4,049,495 and 4,137,322 disclose the fermentative production of a natural product, now called compactin, having an inhibitory effect on cholesterol biosynthesis. Compactin has been shown to have a complex structure which includes a mevalonolactone moiety (Brown et al, J. Chem. Soc. Perkin I, (1976), (1165).
U.S. Pat. No. 4,255,444 to Oka, et al, discloses several synthetic derivatives of mevalonolactone having antilipidemic activity.
U.S. Pat. Nos. 4,198,425 and 4,262,013 to Mitsue, et al, disclose aralkyl derivatives of mevalonolactone which are useful in the treatment of hyperlipidemia.
U.S. Pat. No. 4,375,475 to Willard, et al, discloses certain substituted 4-hydroxytetrahydropyran-2-ones which, in the 4(R)-trans stereoisomeric form, are inhibitors of cholesterol bioisynthesis.
U.S. Pat. No. 4,647,576 to Hoefle, et al, discloses certain trans-6-[2-[(substituted)-pyrrol-1-yl]alkyl]tetrahydro-4-hydroxypyran-2-on es and the corresponding lactone ring-opened acids as inhibitors of cholesterol biosynthesis.
U.S. Pat. No. 4,681,893 to Roth discloses certain trans-6-[[(2-, 3-, or (4-carboxamido-substituted)pyrool-1-yl]alkyl- or alkenyl]tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis.